Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance

Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance

  • GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry 9, 137–150 (2022).

    Article 
    PubMed Central 

    Google Scholar
     

  • Ulrich-Lai, Y. M. & Herman, J. P. Neural regulation of endocrine and autonomic stress responses. Nat. Rev. Neurosci. 10, 397–409 (2009).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Cacioppo, J. T. et al. The neuroendocrinology of social isolation. Annu. Rev. Psychol. 66, 733–767 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • O’Connor, D. B., Thayer, J. F. & Vedhara, K. Stress and health: a review of psychobiological processes. Annu. Rev. Psychol. 72, 663–688 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Devarbhavi, H. et al. Global burden of liver disease: 2023 update. J. Hepatol. 79, 516–537 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Russ, T. C. et al. Association between psychological distress and liver disease mortality: a meta-analysis of individual study participants. Gastroenterology 148, 958–966.e4 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Steel, J. L. et al. Depression, immunity, and survival in patients with hepatobiliary carcinoma. J. Clin. Oncol. 25, 2397–2405 (2007).

    Article 
    PubMed 

    Google Scholar
     

  • Wu, Y. et al. Psychological distress and eustress in cancer and cancer treatment: advances and perspectives. Sci. Adv. 8, eabq7982 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Antoni, M. H., Moreno, P. I. & Penedo, F. J. Stress management interventions to facilitate psychological and physiological adaptation and optimal health outcomes in cancer patients and survivors. Annu. Rev. Psychol. 74, 423–455 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Miller, B. M., Oderberg, I. M. & Goessling, W. Hepatic nervous system in development, regeneration, and disease. Hepatology 74, 3513–3522 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Jensen, K. J., Alpini, G. & Glaser, S. Hepatic nervous system and neurobiology of the liver. Compr. Physiol. 3, 655–665 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Adori, C. et al. Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging. Sci. Adv. 7, eabg5733 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Lee, J. A. et al. Disappearance of hepatic parenchymal nerves in human liver cirrhosis. Gut 33, 87–91 (1992).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zsombok, A., Desmoulins, L. D. & Derbenev, A. V. Sympathetic circuits regulating hepatic glucose metabolism: where we stand. Physiol. Rev. 104, 85–101 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Puschel, G. P. Control of hepatocyte metabolism by sympathetic and parasympathetic hepatic nerves. Anat. Rec. A Discov. Mol. Cell Evol. Biol. 280, 854–867 (2004).

    Article 
    PubMed 

    Google Scholar
     

  • Kjaer, M. et al. No reinnervation of hepatic sympathetic nerves after liver transplantation in human subjects. J. Hepatol. 20, 97–100 (1994).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Laryea, M. et al. Metabolic syndrome in liver transplant recipients: prevalence and association with major vascular events. Liver Transpl. 13, 1109–1114 (2007).

    Article 
    PubMed 

    Google Scholar
     

  • Bogdanos, D. P., Gao, B. & Gershwin, M. E. Liver immunology. Compr. Physiol. 3, 567–598 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, X. et al. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat. Rev. Cancer 21, 541–557 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Trefts, E., Gannon, M. & Wasserman, D. H. The liver. Curr. Biol. 27, R1147–R1151 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Sun, R. et al. Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis. J. Hepatol. 77, 453–466 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Marszalek-Grabska, M. et al. Kynurenine emerges from the shadows—current knowledge on its fate and function. Pharmacol. Ther. 225, 107845 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Platten, M., Wick, W. & Van den Eynde, B. J. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 72, 5435–5440 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Trezeguet, V., Fatrouni, H. & Merched, A. J. Immuno-metabolic modulation of liver oncogenesis by the tryptophan metabolism. Cells 10, 3469 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Xu, B. et al. Metabolic rewiring of kynurenine pathway during hepatic ischemia–reperfusion injury exacerbates liver damage by impairing NAD homeostasis. Adv. Sci. 9, e2204697 (2022).

    Article 

    Google Scholar
     

  • Antoniuk, S. et al. Chronic unpredictable mild stress for modeling depression in rodents: meta-analysis of model reliability. Neurosci. Biobehav. Rev. 99, 101–116 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Liu, K. et al. Metabolic stress drives sympathetic neuropathy within the liver. Cell Metab. 33, 666–675.e4 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Cervenka, I., Agudelo, L. Z. & Ruas, J. L. Kynurenines: tryptophan’s metabolites in exercise, inflammation, and mental health. Science 357, eaaf9794 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Liu, L. et al. Quantitative analysis of NAD synthesis–breakdown fluxes. Cell Metab. 27, 1067–1080.e5 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wang, D. et al. Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage. Acta Pharm. Sin. B 11, 763–780 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Russell, G. & Lightman, S. The human stress response. Nat. Rev. Endocrinol. 15, 525–534 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Fries, G. R. et al. Molecular pathways of major depressive disorder converge on the synapse. Mol. Psychiatry 28, 284–297 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Anisman, H., Ravindran, A. V., Griffiths, J. & Merali, Z. Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features. Mol. Psychiatry 4, 182–188 (1999).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Philipp, M. & Hein, L. Adrenergic receptor knockout mice: distinct functions of 9 receptor subtypes. Pharmacol. Ther. 101, 65–74 (2004).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Tank, A. W. & Lee Wong, D. Peripheral and central effects of circulating catecholamines. Compr. Physiol. 5, 1–15 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • London, E., Bloyd, M. & Stratakis, C. A. PKA functions in metabolism and resistance to obesity: lessons from mouse and human studies. J. Endocrinol. 246, R51–R64 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zhang, H., Kong, Q., Wang, J., Jiang, Y. & Hua, H. Complex roles of cAMP-PKA-CREB signaling in cancer. Exp. Hematol. Oncol. 9, 32 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Xue, C. et al. Tryptophan metabolism in health and disease. Cell Metab. 35, 1304–1326 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Carambia, A. & Herkel, J. Dietary and metabolic modulators of hepatic immunity. Semin. Immunopathol. 40, 175–188 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360, eaan5931 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tian, P. et al. Early life gut microbiota sustains liver-resident natural killer cells maturation via the butyrate–IL-18 axis. Nat. Commun. 14, 1710 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hong, J. Y. et al. Long-term programming of CD8 T cell immunity by perinatal exposure to glucocorticoids. Cell 180, 847–861.e15 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zhang, S. et al. Neuroendocrine regulation of stress-induced T cell dysfunction during lung cancer immunosurveillance via the kisspeptin/GPR54 signaling pathway. Adv. Sci. 9, e2104132 (2022).

    Article 

    Google Scholar
     

  • Lelou, E. et al. The role of catecholamines in pathophysiological liver processes. Cells 11, 1021 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Du Preez, A. et al. Chronic stress followed by social isolation promotes depressive-like behaviour, alters microglial and astrocyte biology and reduces hippocampal neurogenesis in male mice. Brain Behav. Immun. 91, 24–47 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Leng, L. et al. Menin deficiency leads to depressive-like behaviors in mice by modulating astrocyte-mediated neuroinflammation. Neuron 100, 551–563.e7 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Wang, Y. et al. Inhibition of activated astrocyte ameliorates lipopolysaccharide-induced depressive-like behaviors. J. Affect. Disord. 242, 52–59 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Seehawer, M. et al. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 562, 69–75 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ma, S. et al. Identification of a small-molecule Tim-3 inhibitor to potentiate T cell-mediated antitumor immunotherapy in preclinical mouse models. Sci. Transl. Med. 15, eadg6752 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Chen, C. et al. Soluble Tim-3 serves as a tumor prognostic marker and therapeutic target for CD8+ T cell exhaustion and anti-PD-1 resistance. Cell Rep. Med. 5, 101686 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Liu, C. et al. Environmental eustress modulates beta-ARs/CCL2 axis to induce anti-tumor immunity and sensitize immunotherapy against liver cancer in mice. Nat. Commun. 12, 5725 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Luo, X. et al. SOX12 facilitates hepatocellular carcinoma progression and metastasis through promoting regulatory T-cells infiltration and immunosuppression. Adv. Sci. 11, e2310304 (2024).

    Article 

    Google Scholar
     

  • Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hu, H. et al. Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell 175, 1591–1606.e19 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Ding, Y. et al. Intrinsic PD-L1 promotes antitumor activity of CD8+ cytotoxic T lymphocytes via in cis interaction with CD80. Cancer Commun. 42, 784–788 (2022).

    Article 

    Google Scholar